APPLICANT'S DESCRIPTION This PPG renewal involves investigators from the University of Southern California participating in a multidisciplinary and highly interactive research effort on understanding the basic mechanisms involved in gene delivery in order to develop gene therapy approaches for the treatment of cancer. The investigators are drawn from both basic science and clinical departments. The Program consists of five research Projects and two Core resources. The theme of this Program is to apply concepts and techniques developed in molecular genetics, molecular biology, tumor biology, basic immunology and clinical immunology to illuminate poorly understood mechanisms involved in the delivery and expression of genes by retroviral vectors. Dr. W. French Anderson is engineering the ecotropic murine leukemia virus envelope protein to bind to specific cell surface receptors and to thereby direct the vectors to specific target cells. Dr. Nori Kasahara will place replication of retroviruses under the control of a cellular transcriptional promoter thus limiting replication to cells that can activate the promoter. Dr. Donald Kohn will study gene expression from retroviral and lentiviral vectors after gene transfer into HSC. He will analyze mechanisms of augmented expression from retroviral vectors produced by removal, mutagenesis or insertion of defined DNA segments. Drs. Amy Lee and Gunther Dennert will test directly in retroviral vectors the efficacy of the glucose-starvation inducible GRP78 promoter regulatory elements, alone or in combination with the hypoxic response element, to drive targeted and long-term expression of therapeutic genes in mammary carcinoma models in vivo. Dr. Robertson Parkman will establish that the transplantation of positively selected HSC transduced with lentivirus vectors can result in the lymphohematopoietic reconstitution of myeloablative recipients. The two Core resources include administration and viral vector development and these are integrated and interdependent. Finally, the Program is integrated in the University research community and in particular with the USC Gene Therapy Program, a partnership between the Norris Comprehensive Cancer Center/Institute for Genetic Medicine Joint Gene Therapy Program and the Gene Therapy Program of Childrens' Hospital Los Angeles.